8,8-Disubstituted-6-methylergolines and related compounds

ABSTRACT

8,8-Disubstituted-6-methylergolines and 9-ergolenes, prepared by alkylation of lysergic, isolysergic or their 9,10-dihydro analogues, optionally followed by chemical modification of an 8-substituent.

BACKGROUND OF THE INVENTION

Compounds based on the ergoline ring system ##STR1## have a suprisingvariety of pharmaceutical activities. For example, lysergic andisolysergic acid are 8-carboxy-6-methyl-9-ergolenes. The amides oflysergic acid, many of which have valuable and unique pharmacologicproperties, include the naturally occurring oxytocicalkaloids--ergocornine, ergokryptine, ergonovine, ergocristine,ergosine, ergotamine, etc.--and synthetic oxytocics such as methergine,as well as the synthetic hallucinogen--lysergic acid diethylamide orLSD. The corresponding amides of 6-methyl-8-carboxyergoline, knowngenerically as dihydroergot alkaloids, are oxytocic agents of lowerpotency and also lower toxicity than the ergot alkaloids themselves.Recently, it has been found by Clemens, Semonsky, Meites and theirvarious co-workers, that many ergot-related drugs have activity asprolactin inhibitors including ergocornine, dihydroergocornine,2-bromo-α-ergokryptine and d-6-methyl-8-cyanomethylergoline. Referencesembodying some of the newer findings in this field of ergolinepharmacology are the following: Nagasawa and Meites, Proc. Soc. Exp't'l.Biol. Med, 135, 469 (1970); Lutterbeck et al., Brit. Med. J., 228, (July24, 1971); Heuson et al., Europ. J. Cancer, 353 (1970); Coll. Czech,Chem. Commun., 33, 577 (1968 ); Nature, 221,666 (1969); Seda et al., J.Reprod. Fert., 24, 263 (1971); Mantle and Finn, id, 441; Semonsky andco-workers, Coll. Czech. Chem. Comm., 36, 2200 (1971); Schaar andClemens, Endocr., 90, 285-8 (1972); Clemens and Schaar, Proc. Soc. Exp.Biol. Med., 139, 659-662 (1972) and Sweeney, Clemens, Kornfeld andPoore, 64th Annual Meeting, American Association Cancer Research, April1973. Recently issued patents in the field of erogoline derivatives orlysergic acid derivatives include the following: U.S. Pat. No.3,704,233, U.S. Pat. No. 3,709,891, U.S. Pat. No. 3,585,201, U.S. Pat.No. 3,666,762, U.S. Pat. No. 3,586,683, U.S. Pat. No. 3,717,640, andU.S. Pat. No. 3,592,816.

Only a few 8,8-disubstituted ergolines have been prepared. A majority ofthese compounds also have a substituent on the indole nitrogen thusyielding a 1,8,8-tri-substituted derivative. For example, Baker et al.publishing in Molecular Pharmacology, 9, 23 (1973) reported1,8-dimethyl-D-lysergic acid p-bromanilide. This compound showed nohallucinogenic activity unlike D-lysergic acid p-bromanilide. The samecompound is mentioned in Science, 178, 614 (1972). Troxler and Hofmann,Helvetica Chemica Acta, 40, 1722 (1957) prepared the 8-methyl derivativeof D-isolysergic acid diethylamide, stating that they were, however,unable to obtain substitution at C₈ using dihydrolysergic acid methylester and the alkylating agent used successfully with lysergic aciditself; to wit, methyliodide and potassium amide. These authors alsoprepared 8-ethyl-D-isolysergic acid diethylamide and the1,8-dimethyl-D-isolysergic acid diethylamide. There is no mention in theliterature of an 8,8-disubstituted-9-ergolene in which the substituentsat 8 are other than amide groups and in which the 1-position is notsubstituted. 6-Methyl-8,8-disubstituted ergolines are not mentioned inthe literature.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula ##STR2## wherein R isalk, carbo(C₁ -_(C13))alkoxy, Cl or Br; R' is carboxyl, carbo(C₁-_(C3))alkoxy, of CH₂ Z,

wherein alk is (C₁ -C₃)alkyl and

Z is H, OH, CN, OSO₂ alk, Y-phenyl, or Y-alk,

wherein Y is S or O; and

R" and R'" when taken singly are H; and, when taken together with thecarbon atoms to which they are attached, form a double bond.

Also included within the scope of this invention arepharmaceutically-acceptable acid addition salts of compounds accordingto Formula 1 formed with a non-toxic acid. Thesepharmaceutically-acceptable salts include salts derived from inorganicacids such as: hydrochloric acid, nitric acid, phosphoric acid, sulfuricacid, hydrobromic acid, hydriodic acid, nitrous acid, phosphorous acidand the like, as well as salts derived from nontoxic organic acids suchas aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxy alkanoic and alkandioic acids, aromatic acids, aliphaticand aromatic sulfonic acids, etc. Such pharmaceutically-acceptable saltsthus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride,acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, mandelate,butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,phthalate, terephthalate, benzenesulfonates, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, malate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts.

In the above formula, (C₁ -C₃)alkyl includes the groups methyl, ethyl,propyl, and isopropyl. The term (C₁ -C₃)alkoxy thus includes the termsmethoxy, ethoxy, and propoxy and the term carbo(C₁ -C₃)alkoxy includesthe terms carbomethoxy, carboethoxy, carbopropoxy and carboisopropoxy.In the above formula, when R" and R'" are hydrogen, the compound isdenominated an ergoline, but when R" and R'", when taken together with acarbon atom to which they are attached, form a double bond, the compoundis denominated a 9-ergolene. The following compounds exemplify the scopeof our invention:

D-6-methyl-8α-ethyl-8β-carbomethoxyergoline sulfate

D-6-methyl-8α-isopropyl-8β-chloroergoline phosphate

D-8α-isopropyl lysergic acid

D-8α-ethyl lysergic acid

D-8α-ethyl dihydrolysergic acid

D-8β-methylisolysergic acid

D-6-methyl-8β-ethyl-8α-carbo-n-propoxy-9-ergolene maleate

D-6-methyl-8β-hydroxymethyl-8α-ethyl-9-ergolene succinate

D-6-methyl-8β-cyanomethyl-8α-carboethoxy-9-ergolene

D-6-methyl-8α-cyanomethyl-8β-n-propylergoline hydrochloride

D-6-methyl-8β-mesyloxymethyl-8α-bromoergoline tartrate

D-6-methyl-8α-methoxymethyl-8β-carboethoxyergoline citrate

D-6-methyl-8β-ethoxymethyl-8α-carboisopropoxy-9-ergolene lactate

D-6-methyl-8α-phenoxymethyl-8β-carbomethoxyergoline methane sulfonate

D-6-methyl-8β-phenoxymethyl-8α-carboethoxy-9-ergolene

D-8α-phenylmercaptomethyl lysergic acid

D-8α-methylmercaptomethyl lysergic acid toluene sulfonate

D-8β-n-propylmercaptomethyl isolysergic acid,

and the like. The compounds of this invention are white crystallinesolids, as are their acid addition salts formed with non-toxic acids.Compounds in which one of R or R' is carbo(C₁ -C₃)alkoxy, are preparedby alkylating an ester of lysergic or isolysergic acid or ofdihydrolysergic or dihydroisolysergic acid with an alkylating agent ofthe formula R""(CH₂)_(n) X wherein R"" is CH₃, CN--CH₂ or ##STR3## n is0, 1 or 2 and X is a halogen according to the following reaction scheme:##STR4##

A strong non-hydrolytic base such as sodium amide, potassium amide,lithium tetramethylpiperidide, potassium diisopropyl amide and the likeare used to replace the hydrogen at C₈ to form an anion, which anionthen reacts with the alkylating agent R""(CH₂)_(n) X. Compoundsaccording to formula I above in which R is carboxyl are prepared byhydrolyzing the corresponding carbo(C₁ -C₃)alkoxy compound. Compounds inwhich R' is CH₂ Z wherein Z is hydroxyl are prepared by lithium aluminumhydride reduction of the corresponding ester grouping. Compounds inwhich Z is cyanide are prepared by first forming the mesylate ester ofthe hydroxymethyl derivative (compounds wherein R' is CH₂ Z and Z is OH)and then replacing the mesylate radical with cyanide by use of sodiumcyanide. Compounds in which Z is Y-phenyl or Y-alk are prepared insimilar fashion by reacting the mesylate ester with phenol orphenylmercaptan, a lower alkanol or a lower alkylmercaptan. Finally,compounds in which R is Cl or Br and R' is carbo(C₁ -C₃)alkoxy areprepared by reacting the alkali metal salt of a lysergic,dihydrolysergic or isolysergic acid corresponding thereto withp-toluenesulfonylchloride, p-toluenesulfonylbromide or other acylchloride or bromide. In this reaction, suprisingly, the ester group doesnot replace the anion but the halogen atom.

It will be apparent to those skilled in the art from the above generaldirections that individual combinations of substituents for R and R' canbe achieved by altering the order in which reactions are carried outinvolving a carbo(C₁ -C₃)alkoxy group after the initial reaction withthe alkylating agent, R""(CH₂)_(n) X.

This invention is further illustrated by the following specificexamples.

EXAMPLE 1 PREPARATION OF D-6,8-DIMETHYL-8-CARBOMETHOXYERGOLINE

A solution containing 11.5 g. of tetramethylpiperidine in 100 ml. oftetrahydrofuran (THF) was cooled to about -10° C. Fifty ml. of n-butyllithium as a 1.6 molar solution in hexane was added at such a rate thatthe temperature remained in the range -10° to -2° C. The resultingmixture was stirred with cooling under a nitrogen atmosphere for about20 minutes. Next, a solution of 5.7 g. of methyl dihydrolysergate in 125ml. of THF was added to the reaction mixture at a rate sufficient tokeep the temperature in the range -10° to -5° C. The resulting reactionmixture was stirred with cooling under a nitrogen atmosphere for about15 minutes, after which time a solution of 3.6 g. of methyl iodide in 50ml. of THF was added rapidly. The temperature rose from -9° C. to about1° C., and was allowed to continue to rise to 6° C. over a 35 minuteperiod. The reaction mixture was then decomposed by the addition ofaqueous acetic acid. The acidic layer was diluted with water and thenmade basic by the addition of solid sodium bicarbonate.D-6,8-dimethyl-8-carbomethoxyergoline formed in the above reaction wasinsoluble in the alkaline layer and separated. The separated compoundwas extracted into chloroform. The chloroform layer was separated anddried, and the chloroform removed by evaporation. Thin layerchromatography of the resulting residue indicated two spots less polarthen the methyldihydrolysergate starting material. These spotscorresponded to the two isomers, the α-methyl and the β-methyl isomers,produced by the above reaction. The residue was redissolved inchloroform and filtered through 250 g. of florisil to yield a mixture ofthe two isomers having the structure ofD-6,8-dimethyl-8-carbomethoxyergoline. This mixture was chromatographedover 250 g. of florisil, using a chloroform-ether solvent mixture as theeluant, to yieldD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxyergolinemelting at about 136°-8° C. in an 18 percent yield and the corresponding8.[.α.]..Iadd.β.Iaddend.-methyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxyisomer melting at about 223°-5° C. with decomposition representing abouta 35 percent yield.

Analysis forD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxyergoline:

Calc.: C, 72.46; H, 7.43; N, 9.39; Found: C, 72.29; H, 7.28; N, 9.43.

Analysis forD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxyergoline:

Calc.: C, 72.46; H, 7.43; N, 9.39; Found: C, 72.73; H, 7.69; N, 9.64.

EXAMPLE 2 PREPARATION OFD-6,8.[.β.]..Iadd.α.Iaddend.-DIMETHYL-8.[.α.]..Iadd..beta..Iaddend.-HYDROXYMETHYLERGOLINE

A solution was prepared containing 700 mg. ofD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxyergolinein 100 ml. of THF. 700 mg. of lithium aluminum hydride were added insmall portions. The resulting mixture was stirred at ambient temperatureunder a nitrogen atmosphere for about three-quarters of an hour. Thereaction mixture was cooled and excess lithium aluminum hydridedecomposed by the addition of ethyl acetate. The reaction mixture wasthen diluted with water andD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-hydroxymethylergolineformed in the above reaction extracted into chloroform. The chloroformlayer was separated and dried. Evaporation of the solvent left as aresidueD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-hydroxymethylergolinewhich melted at about 219°-221° C. with decomposition afterrecrystallization from an ether-hexane solvent mixture.

Analysis Calc.: C, 75.52; H, 8.20; N, 10.36; Found: C, 75.46; H, 8.24;N, 10.08.

The above reduction was repeated withD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxyergolineto prepareD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-hydroxymethylergolinemelting at about 222°-4° C. with decomposition after recrystallizationfrom ethyl acetate.

Analysis Calc.: C, 75.52; H, 8.20; N, 10.36; Found: C, 75.43; H, 8.37;N, 10.11.

EXAMPLE 3 PREPARATION OFD-6,8.[.α.]..Iadd.β.Iaddend.-DIMETHYL-8.[.β.]..Iadd..alpha..Iaddend.-MESYLOXYMETHYLERGOLINE

Following the procedure of Example 2, 2.1 g. ofD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxyergolinewere reduced to the corresponding 8.[.β.]..Iadd.α.Iaddend.-hydroxymethylderivative with lithium aluminum hydride. The crude product of thereaction was dissolved in 50 ml. of pyridine and 0.9 ml. ofmethanesulfonyl chloride (mesyl chloride) were added in dropwisefashion. The reaction mixture was stoppered, stirred at ambienttemperature for about 20 minutes, and was then poured into aqueoussodium bicarbonate.D-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-mesyloxymethylergolineformed in the above reaction was extracted with chloroform. Separationand drying of the chloroform layer followed by evaporation of thechloroform yielded a residue which provided purifiedD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-mesyloxymethylergolinemelting at 176°-8° C. after recrystallization from ethanol.

Analysis Calc.: C, 62.04; H, 6.94; N, 8.04; Found: C, 61.98; H, 7.10; N,7.96.

The above reaction was repeated with theD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd.62.Iaddend.-carbomethoxyergoline as a starting material.D-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-mesyloxymethylergolinethus prepared melted at about 160° C. with decomposition afterrecrystallization from ether.

Analysis Calc.: C, 62.04; H, 6.94; N, 8.04; S, 9.20; Found: C, 61.75; H,7.20; N, 8.31; S, 9.19.

EXAMPLE 4 PREPARATION OFD-6,8.[.β.]..Iadd.α.Iaddend.-DIMETHYL-8.[.α.]..Iadd..beta..Iaddend.-CYANOMETHYLERGOLINE

A reaction mixture was prepared from 200 mg. ofD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-mesyloxymethylergoline,200 mg. of sodium cyanide in 25 ml. of dimethylsulfoxide (DMSO). Themixture was heated at 100°-120° C. for about 2.25 hours. The reactionmixture was then poured into water andD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-cyanomethylergolineformed in the above reaction was extracted with ethyl acetate. The ethylacetate extract was separated and dried and the ethyl acetate evaporatedtherefrom. Recrystallization of the resulting residue from ethanolyieldedD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-cyanomethylergolinemelting at 250°-5° C. with decomposition.

Analysis Calc.: C, 77.38; H, 7.58; N, 15.04; Found: C, 77.58; H, 7.78;N, 15.12.

Following the above procedure,D-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-mesyloxymethylergolinewas reacted with sodium cyanide to yield the corresponding8.[.β.]..Iadd.α.Iaddend.-cyanomethyl compound. The compound wasseparated from the starting material by chromatography on florisil usingchloroform containing 2 percent ethanol as an eluant.D-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-cyanomethylergolinethus prepared melted at 195°-6° C. after recrystallization of materialpurified by chromatography from a benzene-hexane solvent mixture.

Analysis Calc.: C, 77.38; N, 7.58; N, 15.04; Found: C, 77.72; H, 7.57;N, 14.63.

EXAMPLE 5 PREPARATION OFD-6,8.[.β.]..Iadd.α.Iaddend.-DIMETHYL-8.[.α.]..Iadd..beta..Iaddend.-PHENYLMERCAPTOMETHYLERGOLINE

Following the procedure of Example 4,D-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-mesyloxymethylergolinewas reacted with the sodium salt of thiophenol in DMF to yieldD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-phenylmercaptomethylergoline.The reaction mixture was subjected to a 5 percent potassium hydroxidewash to remove any unreacted thiophenol.D-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd.β.Iaddend.-phenylmercaptomethylergolinethus formed was purified by chromatography over florisil usingchloroform containing 2 percent ethanol as an eluant. Recrystallizationof the residue resulting from evaporation of the solvent fromchromatographic fractions shown to containD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-phenylmercaptomethylergolineby thin layer chromatography yielded purified material melting at157°-8° C. after recrystallization from ethanol.

Analysis Calc.: C, 76.20; H, 7.23; N, 7.73; S, 8.84; Found: C, 75.99; H,7.04; N, 7.50; S, 8.99.

The same procedure was carried out on the corresponding6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd.α.Iaddend.-phenylmercaptomethylergolinewhich melted at 217°-8° C. with decomposition after recrystallizationfrom ethanol.

Analysis Calc.: C, 76.20; H, 7.23; N, 7.73; Found: C, 76.14; H, 7.39; N,7.79.

EXAMPLE 6 PREPARATION OF D-6,8,8-TRIMETHYLERGOLINE

About 215 mg. ofD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-phenylmercaptomethylergolinewere reacted with about 3 g. of wet Raney nickel in 25 ml. of 95 percentethanol as a solvent. The reaction mixture was heated to refluxingtemperature under a nitrogen atmosphere for about 35 minutes. Themixture was then filtered while hot and the catalyst washed well with 95percent ethanol. Evaporation of the filtrate yieldedD-6,8,8-trimethylergoline as a residue. The compound melted at 221°-2°C. after recrystallization from methanol.

Analysis Calc.: C, 80.27; H, 8.72; N, 11.01; Found: C, 80.33; H, 8.84;N, 11.21.

The procedure was repeated with the corresponding8.[.α.]..Iadd.β.Iaddend.-phenylmercaptomethyl isomer to yield the sameD-6,8,8-trimethylergoline having an identical melting point.

EXAMPLE 7 PREPARATION OF D-6-METHYL-8-CARBOMETHOXY-8-CYANOMETHYLERGOLINE

Following the procedure of Example 1, methyl 9,10-dihydrolysergate wasalkylated with chloroacetonitrile in the presence oftetramethylpiperidine and n-butyl lithium in THF as a solvent to yield amixture of the 8α-carbomethoxy-8β-cyanomethyl and8α-cyanomethyl-8β-carbomethoxy isomers. The residue containing theisomer mixture prepared by evaporation of the chloroform extract of thework up of the original reaction mixture was subjected to chromatograhyover florisil using chloroform containing 5 percent ethanol as aneluant. Fractions shown to contain each isomer by thin layerchromatography were combined, the solvent evaporated therefrom and theresidue recrystallized.D-6-methyl-8.[.β.]..Iadd.α.Iaddend.-cyanomethyl-8.[.α.]..Iadd.β.Iaddend.-carbomethoxyergolinewas the less polar of the two isomers and was found in the earlierfractions. This isomer melted at 179°-180° C. after recrystallizationfrom an ether-hexane solvent mixture.

Analysis.: C, 70.57; H, 6.55; N, 12.99; Found: C, 70.41; H, 6.55; N,13.19.

The isomericD-6-methyl-8.[.α.]..Iadd.β.Iaddend.-cyanomethyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxyergolinewas more polar than its isomer but less polar than starting material.The compound melted at 220°-3° C. with decomposition after separation bychromatography and recrystallization from an ether-hexane solventmixture.

Analysis Calc.: C, 70.57; H, 6.55; N, 12.99; Found: C, 70.32; H, 6.79;N, 13.27.

EXAMPLE 8 PREPARATION OF D-6-METHYL-8,8-DICARBOMETHOXYERGOLINE

Following the procedure of Example 1, methyl 9,10-dihydrolysergate wasreacted with methylchlorocarbonate in the presence oftetramethylpiperidine and n-butyl lithium in THF solution.D-6-methyl-8,8-dicarbomethoxyergoline formed in the above reaction wasisolated as in Example 1 and was purified by chromatography overflorisil employing a 1:1 chloroform-ether solvent mixture as the eluant.Fractions shown to contain D-6-methyl-8,8-dicarbomethoxyergoline by thinlayer chromatography were combined, and the residue, obtained byevaporation of the solvent, recrystallized from an ether-hexane solventmixture to yield crystalline material melting at about 164°-5° C.

Analysis Calc.: C, 66.65; H, 6.48; N, 8.18; Found: C, 66.78; H, 6.51; N,7.95.

EXAMPLE 9 PREPARATION OF D-6-METHYL-8-CHLORO-8-CARBOMETHOXYERGOLINE

Following the procedure of Example 1, methyl 9,10-dihydrolysergate wasreacted with p-toluenesulfonyl chloride in the presence oftetramethylpiperidine and n-butyl lithium in the solution.D-6-methyl-8-chloro-8-carbomethoxyergoline formed in the above reactionwas isolated by the procedure of Example 1 and was purified bychromatography over florisil using chloroform as the eluant. The majorchromatographic fraction from the initial chromatography was less polarthan starting material. This fraction was rechromatographed overflorisil using chloroform and chloroform ethanol mixtures as the eluantsolution. Fractions shown to containD-6-methyl-8-chloro-8-carbomethoxyergoline by thin layer chromatographywere combined and the solvent evaporated therefrom. Recrystallization ofthe residue from methanol yieldedD-6-methyl-8-chloro-8-carbomethoxyergoline melting at 192°-3° C. withdecomposition.

Analysis Calc.: C, 64.05; H, 6.01; N, 8.77; Cl, 11.12; Found: C, 64.16;H, 5.72; N, 9.00; Cl, 10.86.

EXAMPLE 10 PREPARATION OFD-2,13-DIBROMO-6,8.[.α.]..Iadd.β.Iaddend.-DIMETHYL-8.[.β.]..Iadd.α.Iaddend.-CARBOMETHOXYERGOLINE

A solution was prepared containing 825 mg. ofD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxyergolineprovided by the procedure of Example 1 in 25 ml. of acetic acid and 15ml. of chloroform. The solution was cooled to about 0° C. 1.7 g. ofpyridine perbromide hydrobromide were added in portions. The reactionmixture was stirred under a nitrogen atmosphere and cooled for aboutone-half hour and then allowed to warm to room temperature, at whichtemperature it was stirred for an additional 2.5 hours. The reactionmixture was then poured into aqueous ammonium hydroxide solution.D-2,13-dibromo-6,8.[.α.]..Iadd.β-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxyergolineformed in the above reaction was extracted with ethyl acetate. The ethylacetate layer was separated, washed with water and saturated aqueoussodium chloride and then dried. Evaporation of the solvent therefromyielded a residue which was purified by chromatography using chloroformcontaining 1 percent ethanol as the eluant. Fractions shown by thinlayer chromatography to containD-2,13-dibromo-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxyergolinewere combined and the solvent removed therefrom by evaporation. D-2,13-dibromo-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxyergolinethus prepared melted at 253°-5° C. with decomposition afterrecrystallization from ether.

Analysis Calc.: C, 47.39; H, 4.42; N, 6.14; Br, 35.03; Found: C, 47.60;H, 4.21; N, 6.11; Br, 34.73.

EXAMPLE 11 PREPARATION OFD-6,8.[.α.]..Iadd.β.Iaddend.-DIMETHYL-8.[.β.]..Iadd..alpha..Iaddend.-CARBOMETHOXY-13-BROMOERGOLINE

A solution was prepared containing 450 mg. ofD-2,13-dibromo-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxyergolineprovided by the procedure of Example 10 in 75 ml. of methanol. About 2g. of cobalt chloride were added and the suspension cooled to about -20°C., and 1.5 g. of sodium borohydride were added in portions. Stirringwas continued at -20° to -30° C. for about one-half hour. The reactionmixture was then diluted with water andD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxy-13-bromoergolineformed in the reaction extracted with ethyl acetate. The organic layerwas separated, washed with water and saturated sodium chloride and thendried. Evaporation of the ethyl acetate therefrom yielded a residuewhich was purified by filtration through florisilD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxy-13-bromoergoline thus prepared wasrecrystallized from an ether-hexane solvent mixture to yield materialmelting at 228°-9° C. with decomposition.

Analysis Calc.: C, 57.30; H, 5.61; N, 7.43; Br, 21.28; Found: C, 57.43;H, 5.34; N, 7.57; Br, 20.06 and 20.32.

EXAMPLE 12 PREPARATION OFD-6,8.[.β.]..Iadd.α.Iaddend.-DIMETHYL-8.[.α.]..Iadd..beta..Iaddend.-CARBOMETHOXY-9-ERGOLENE

A solution of 10 g. of diisopropylamine in 150 ml. of THF was preparedand cooled to about -75° C. 60 ml. of an n-butyl lithium solution (about1.6 M. in hexane) were added slowly thereto. Next, a solution of 7.0 g.of methyl lysergate in 120 ml. of THF was added in dropwise fashion. Theresulting precipitate increased the viscosity of the solution, and anadditional 120 ml. of THF were added. Next, a solution of 12.4 ml. ofmethyl iodide in 100 ml. of THF was added rapidly. The temperature roseto about -49° C. during this addition. The reaction mixture was treatedwith aqueous acetic acid to decompose the organometallics present, andwas then diluted with water. The aqueous layer was made basic withdilute aqueous ammonium hydroxide.D-6,8β-dimethyl-8α-carbomethoxy-9-ergolene and its8α-methyl-8β-carbomethoxy isomer formed in the above reaction, beinginsoluble in the aqueous alkaline layer, separated and were extractedwith ethyl acetate. The ethyl acetate extract was separated, washed withwater and then with saturated aqueous sodium chloride. After separationand drying, the volatile constituents of the organic layer were removedby evaporation. A chloroform solution of the resulting residue wasfiltered through florisil andD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxy-9-ergolenecrystallized therefrom. Recrystallization ofD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxy-9-ergolenefrom an ether-hexane mixture yielded crystals melting at 117°-19° C.

Analysis Calc.: C, 72.95; H, 6.80; N, 9.45; Found: C, 73.17; H, 6.89; N,9.24.

Chromatography over florisil of the residue resulting from evaporationof the mother liquor from the above recrystallization to dryness usingchloroform as an eluant, yieldedD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxy-9-ergolene,starting material, and in intermediate fractions,D-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxy-9-ergolenemelting at 206°-8° C. with decomposition after recrystallization fromether.

Analysis Calc.: C, 72.95; H, 6.80; N, 9.45; Found: C, 72.68; H, 7.05; N,9.43.

EXAMPLE 13 PREPARATION OFD-6,8.[.β.]..Iadd.α.Iaddend.-DIMETHYL-8.[.α.]..Iadd..beta..Iaddend.-CARBOXY-9-ERGOLENE(α-METHYLISOLYSERGICACID)

About 1 g. ofD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxy-9-ergoleneas the maleate salt (methyl α-methylisolysergate maleate) was refluxedwith about 50 ml. of 10 percent aqueous potassium hydroxide under anitrogen atmosphere for 3 hours. The reaction mixture was cooled andfiltered. The filtrate was made acidic with acetic acid. No precipitatewas formed. The filtrate was then made basic with aqueous ammoniumhydroxide. No precipitate formed upon addition of the ammonium hydroxideeither. The alkaline layer was then extracted with chloroform and thechloroform extract discarded. The alkaline aqueous layer wasconcentrated to about 50 ml. and filtered. The filter cake was washedwith water, ethanol and ether, and dissolved in a small amount ofammonium hydroxide and the resulting solution diluted with water. Theresulting alkaline solution was concentrated in vacuo and then dilutedto a volume of about 50 ml. with water. The solution was cooled at about0° C. overnight and the resulting precipitate separated by filtration.The filter cake was again washed with water, ethanol and ether. Dryingof the filter cake yieldedD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carboxy-9-ergolene(α-methylisolysergic acid) melting at 230°-232° C. with decomposition.

Analysis Calc.: C, 72.32; H, 6.43; N, 9.92; Found: C, 72.04; H, 6.22; N,9.64.

EXAMPLE 14 PREPARATION OFD-6,8.[.β.]..Iadd.α.Iaddend.-DIMETHYL-8.[.α.]..Iadd..beta..Iaddend.-HYDROXYMETHYL-9-ERGOLENE

A solution was prepared containing 4.3 g. ofD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-carbomethoxy-9-ergolenein 100 ml. of THF. 4 g. of lithium aluminum hydride were added inportions while the reaction mixture was cooled in an ice-water bath. Anadditional 100 ml. of THF were added to decrease the viscosity of thereaction mixture. The reaction mixture was stirred at ambienttemperature for about 50 minutes and was then cooled to about 0° C.Excess lithium aluminum hydride and the organometallic salts presentwere decomposed by the addition of ethyl acetate and water. The reactionmixture was diluted with water andD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta.ep-hydroxymethyl-9-ergolene, formed in the above reaction, extracted intochloroform. The chloroform extract was separated and dried, and thechloroform removed therefrom by evaporation in vacuo. The resultingresidue was dissolved in a mixture of chloroform and ether and thesolution slurried with 100 g. of florisil. The florisil was separated byfiltration to yield a residue comprisingD-6,8.[.β.]..Iadd.α.Iaddend.-dimethyl-8.[.α.]..Iadd..beta..Iaddend.-hydroxymethyl-9-ergolenewhich melted above 100° C. after recrystallization from ether or fromether-hexane. The maleate salt thereof was prepared according tostandard procedures and melted at about 200°-2° C. with decompositionafter recrystallization from ethanol.

Analysis Calc.: C, 65.61; H, 6.29; N, 7.29; Found: C, 65.56; H, 6.42; N,7.56.

EXAMPLE 15 PREPARATION OFD-6-METHYL-8-CYANOMETHYL-8-CARBOMETHOXY-9-ERGOLENE

A solution was prepared containing 1.6 g. of diisopropylamine in 20 ml.of THF. The solution was cooled to about -45° C., and 10 ml. of n-butyllithium solution was added to the diisopropylamine solution at such arate that the temperature was maintained in the -45° to -35° C. range.The n-butyl lithium was about 1.6 molar in hexane solution. After theaddition of the n-butyl lithium was complete, the reaction mixture wasstirred and cooled under a nitrogen atmosphere for about 15 minutes. Asolution of 1.15 g. of methyl lysergate in 25 ml. of THF was added at arate such that the temperature of the reaction could be maintained belowabout -35° C. 10 ml. additional THF were added to decrease the viscosityof the solution. The reaction mixture was cooled and stirred under anitrogen atmosphere for about 15 minutes. Next, a solution containing1.2 g. of chloroacetonitrile in 10 ml. of THF was added. The temperatureof the reaction mixture was allowed to warm to about 6° C. during a 25minute period, after which time the reaction mixture was decomposed withaqueous acetic acid. The acidic reaction mixture was diluted with waterand was then made basic by the addition of solid sodium bicarbonate. Thealkaline layer was extracted with chloroform.D-6-methyl-8-cyanomethyl-8-carbomethoxy-9-ergolene, formed in the abovereaction, being insoluble in the alkaline solution, passed into thechloroform layer. The chloroform layer was separated and dried.Evaporation of the chloroform yielded a residue which waschromatographed over florisil using chloroform as the eluant.D-6-methyl-8-cyanomethyl-8-carbomethoxy-9-ergolene was the secondcomponent to be eluted. Fractions shown to contain this compound werecombined, and the solvent evaporated therefrom. The resulting residuewas dissolved in ether, and an ether solution of maleic acid added toform D-6-methyl-8-cyanomethyl-8-carbomethoxy-9-ergolene maleate whichmelted at 158°-161° C. with decomposition after recrystallization fromethanol. The maleate salt was converted back to the free base and astandard acid-base extraction procedure carried out. Re-extraction ofD-6-methyl-8-cyanomethyl-8-carbomethoxy-9-ergolene from the aqueousalkaline layer followed conversion of the resulting residue to thecorresponding maleate salt yieldedD-6-methyl-8-cyanomethyl-8-carbomethoxy-9-ergoline maleate which meltedat 176°-7° C. with decomposition after recrystallization from ether.

Analysis Calc.: C, 63.15; H, 5.30; N, 9.61; Found: C, 63.14; H, 5.05; N,9.87.

EXAMPLE 16 PREPARATION OF SALTS

Salts of the free bases of this invention, other than the maleate saltswhose preparation is illustrated in Examples 14 and 15, are prepared bydissolving the free base in ether and adding an equivalent of a suitablenon-toxic acid, also in ether. The salts thus formed, as for example thesulfate and phosphate salts, are insoluble in ether and can be isolatedby filtration. Alternatively, the amine base can be dissolved in ethanoland an equivalent of the acid added as an ethanolic solution. In thisinstance, since the salts thus formed are soluble in the reactionmixture, they are isolated by evaporation of the solvent in vacuo. Saltswhich can be formed by the above procedure include among others thehydrochloride, sulfate, hydrobromide, phosphate, hydrogen phosphate,dihydrogen phosphate, acetate, maleate, succinate, tartrate, citrate,benzoate, and p-toluene sulfonate salts.

The compounds of this invention are useful as prolactin inhibitorsand/or have activity in the central nervous system. The inhibition ofprolactin secretion by compounds of this invention is evidenced by thefollowing experiment: Adult male rats of the Spraque-Dawley strainweighing about 200 g. were used. All rats were housed in anair-conditioned room with controlled lighting (lights on 6 a.m.-8 pm.)and fed lab chow and water ad libitum.

In each experiment the rats were killed by decapitation, and 150 μlaliquots of serum were assayed for prolactin. Each male rat received anintraperitoneal injection of 2.0 mg. of reserpine in aqueous suspension18 hours before administration of the ergoline derivative. The purposeof the reserpine was to keep prolactin levels uniformly elevated. Theergoline derivatives under test were dissolved in 10 percent ethanol ata concentration of 10 μg/ml, and were injected intraperitoneally at astandard dose of 50 μg/kg. Each compound was administered to a group of10 rats, and a control group of 10 intact males received an equivalentamount of 10 percent ethanol. One hour after treatment, all rats werekilled by decapitation, and the serum was collected and assayed forprolactin as previously described.

The difference between the prolactin level of the treated rats andprolactin level of the control rats, divided by the prolactin level ofthe control rats gives the percent inhibition of prolactin secretionattributable to the compounds of this invention. The table which followsgives prolactin inhibition percentages for a series of compounds comingwithin the scope of Formula I above tested at the 10 μg/rat level. Inthe table, column 1 gives the name of the compound and column 2, thepercent prolactin inhibition.

                  TABLE                                                           ______________________________________                                                                  % Prolactin                                         Name of Compound          Inhibition                                          ______________________________________                                        D-6-methyl-8.[.α.]..Iadd.β.Iaddend.-cyanomethyl-8.[.β.]..I    add.α.Iaddend.-                                                         carbomethoxyergoline      57                                                  D-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha    ..Iaddend.-mesyloxymethylergoline                                                                       64                                                  D-8.[.α.]..Iadd.β.Iaddend.-cyanomethyl-6,8.[.β.]..Iadd..al    pha..Iaddend.-dimethylergoline                                                                          53                                                  D-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha    ..Iaddend.-cyanomethylergoline                                                                          50                                                  D-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha    ..Iaddend.-carbomethoxyergoline                                                                         62                                                  D-8,8.[.α.]..Iadd.β.Iaddend.-dimethyl-6.[.β.]..Iadd..alpha    ..Iaddend.-carbomethoxy-9-ergoline                                                                      45                                                  D-2,13-dibromo-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]    ..Iadd.α.Iaddend.-                                                      carbomethoxyergoline      39                                                  ______________________________________                                    

Other compounds provided by this invention have marginal prolactininhibiting action at the 10 μg/rat level but would have a moresignificant action at higher levels (100 μg to 1 mg)

As prolactin inhibitors, the compounds are useful in the treatment ofinappropriate lactation such as undesired postpartum lactation andgalactorrhea. In addition, they can be used to treat prolactin-dependentadenocarcinomas and prolactin-secreting pituitary tumors as well as thefollowing disorders: Forbes-Albright syndrome, Chiari-Frommel syndrome,gynecomastia itself and gynescomastia occurring as a result ofestrogenic steroid administration for prostatic hypertrophy, fibrocysticdisease of the breast (benign nodules), prophylactic treatment of breastcancer, and breast development resulting from the administration ofpsychotropic drugs, for example, thorazine, or for prostatic hypertrophyitself.

In using the compounds of this invention to inhibit prolactin secretion,an 8,8-disubstituted-6-methylergoline according to Formula I above, or asalt thereof with a pharmaceutically-acceptable acid is suspended incorn oil and the suspension injected parenterally or fed to a femalemammal in amounts varying from 0.01 to 10 mg/kg/day of mammalian weight.Oral administration is preferred. If parenteral administration is used,the injection is preferably by the subcutaneous route using anappropriate pharmaceutical formulation. Other modes of parenteraladministration such as intraperitoneal, intramuscular, or intravenousroutes are equally effective. In particular, with intravenous orintramuscular administration, a soluble pharmaceutically-acceptable saltof an 8,8-disubstituted-6-methylergoline, preferably themethanesulfonate salt, according to Formula I either as the free base orin the form of a salt thereof can also be mixed with standardpharmaceutical excipients and loaded into empty telescoping gelatincapsules or pressed into tablets.

The compounds also have CNS depressant activity and are therefore usefulas general sedatives, etc. For example,D-6-methyl-8.[.α.]..Iadd.β.Iaddend.-carbomethoxy-8.[.β.]..Iadd.α.Iaddend.-cyanomethyl-9-ergolenemaleate, thecorresponding-8.[.α.]..Iadd.β.Iaddend.-carbomethoxy-8β.]..Iadd.α.Iaddend.-methylcompound and the corresponding 8,8-dimethyl derivatives manifest suchactivity.

We claim:
 1. A compound of the formula ##STR5## wherein R is alk,carbo(C₁ -C₃)alkoxy, Cl or Br; R' is carboxyl, carbo(C₁ -C₃)alkoxy, orCH₂ Z, wherein Y is S or O; andR" and R'" when taken singly are H; and,when taken together with the carbon atoms to which they are attached,form a double bond and pharmaceutically-acceptable acid addition saltsthereof formed with non-toxic acids.
 2. The compound according to claim1, said compound beingD-6-methyl-8.[.α.]..Iadd.β.Iaddend.-cyanomethyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxyergoline.3. The compound according to claim 1, said compound beingD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-mesyloxymethylergoline.4. The compound according to claim 1, said compound beingD-6,8.[.α.]..Iadd.β.Iaddend.-cyanomethyl-6,8.[.β.]..Iadd..alpha..Iaddend.-dimethylergoline.5. The compound according to claim 1, said compound beingD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-cyanomethylergoline.6. The compound according to claim 1, said compound beingD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxyergoline.7. The compound according to claim 1, said compound beingD-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd..alpha..Iaddend.-carbomethoxy-9-ergolene.8.D-2,13-dibromo-6,8.[.α.]..Iadd.β.Iaddend.-dimethyl-8.[.β.]..Iadd.α.Iaddend.-carbomethoxyergoline.9. The compound according to claim 1, said compound beingD-6,8,8-trimethylergoline.